Hydroperylene derivatives

ABSTRACT

Compounds of the formula I                    
     are suitable for producing pharmaceuticals for the prophylaxis and therapy of diseases in which high blood platelet aggregations occur.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from Provisional U.S. Application No.60/360,329, filed Feb. 27, 2002, as well as from Federal Republic ofGermany Patent Application No. 10158402.4, filed Nov. 28, 2001.

SUMMARY OF THE INVENTION

The invention relates to hydroperylene derivatives which are formed bythe fungus, DSM 14452, during fermentation, or are subsequentlyderivatized, to processes for preparing them and to their use aspharmaceuticals and inhibitors of blood platelets, as well as to sidnovel fungus itself.

BACKGROUND OF THE INVENTION

Hydroperylene derivatives, such as hexahydroperylene derivatives oroctahydroperylene derivatives, are formed by various microorganisms.Examples of known hydroperylene derivatives are:

Altertoxins I, II and III (M. E. Stark et al. J. Nat. Prod. 49, 866-871,1986),

Alteichin (D. Robeson et al. Experientia, 40, 1248-1250, 1984),

the Alterlosins (A. Stierle et al. J. Nat. Prod. 52, 42-47, 1989) and

Alterperylenol from Alternaria species (T. Okuno et al. TetrahedronLett. 24, 5653-5656, 1983);

Stemphyltoxins and Stemphypyrenol, which are from cultures ofStemphylium botryosum (A. Arnone et al. J. Chem. Soc. Perkin Trans.1,1986, 525-530).

The altertoxins and the stemphyltoxins are phytotoxins, which, as aresult of their mutagenic effect, can also diminish the value of humanfoodstuffs. They have herefore been thoroughly described in more than 70publications (T. J. Schrader et al. Teratog. Carcinog., Mutagen., 21,261-274, 2001). The dangers which emanate from the altertoxins andstemphyltoxins are naturally dealt with in this literature, includingthe wide distribution, and the cancer-causing effect, of thesecompounds, which contain epoxides (oxiranes). In addition to this,alterperylenol has been reported to have a weak telomerase-inhibitingeffect (K-I. Togashi et al. Oncol. Res. 10, 449-453, 1998); however, at30 μM, the IC₅₀ value, which is characteristic for inhibition of theenzyme, is low.

Thromboembolic diseases are the most frequent cause of death,particularly in the western industrial nations. An effective prophylaxisand therapy for these diseases is therefore of exceptional importance. Athrombus is understood as being a blood clot which has been formedintravitally and intravascularly. Thrombi are formed followingthrombocyte aggregation in arteries, in particular. Damage to the bloodvessel wall, retarded blood flow and accelerated clotting all favorthrombus formation. The thrombocytes (blood platelets) are disc-shaped,anucleate blood cells which ensure hemostasis and blood coagulation wheninjury occurs. Thrombocytes bring about hemostasis by means ofaggregation in a complicated process; thrombocyte aggregation isconsequently an essential process for homeotherms. Hypofunction of thethrombocytes leads to severe hemorrhages, even in the case of relativelysmall injuries; on the other hand, an increased tendency towardscoagulation increases the danger of thrombosis and embolism. Sinceplatelet hyperfunction, in particular, frequently has fatalconsequences, several substances have already been employed asinhibitors of thrombocyte aggregation. Those which are well knowninclude acetylsalicylic acid (Aspirin®), ticlopidine (Tiklyd®) and therelated clopidogrel; however, because of side-effects, the use of allthese preparations is restricted. For this reason, there is a great needfor inhibitors of intracellular platelet activation, which can be usedfor the therapy and long-term prophylaxis of arterial thromboembolicevents. Agents of this nature can be employed, for example, inconnection with myocardial infarction, in connection with unstableangina or in connection with strokes.

DETAILED DESCRIPTION OF THE INVENTION

In the endeavor to find effective compounds for preventing or treatingblood coagulation diseases, it has now been found that thioperylenol,which is formed by the fungal strain DSM 14452, and other hydroperylenederivatives, are able to effectively inhibit blood platelet aggregation.

The invention, therefore, relates to a compound of formula I

including all stereoisomeric forms of said compound of formula I,mixtures of said forms and compounds in any ratio, and physiologicallytolerated salts thereof, wherein:

R1, R2, R3, R4, R5, R6, R7, R8, R10 and R11 are independently selectedfrom the group consisting of

hydrogen;

(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of:

—CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted by one, two or three substituentsselected from the group consisting of halogen; —C(O)—OH; —C(O)—O—NH₂;—C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—NH—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—NH₂ and halogen;

(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen;

(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen;

—O—R⁹, in which R⁹ is selected from the group consisting of:(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂, ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

—NH—R⁹, in which R⁹ is as defined above;

—NH—C(O)—H;

—NH—C(O)—R⁹, in which R⁹ is as defined above;

—NH-aryl, in which aryl is unsubstituted or independently substitutedone, two or three times by R⁹, in which R⁹ is as defined above:

═N—OH;

═N—O—R⁹, in which R⁹ is as defined above;

—S—H;

—S—R⁹, in which R⁹ is as defined above;

—S(O)—R⁹, in which R⁹ is as defined above;

—S(O)₂—R⁹, in which R⁹ is as defined above; and

—SO₂, with the following further alternatives to the foregoingdefinition:

a) either R4 and R5 or R10 and R11, together with the carbon atoms towhich they are,respectively, bonded, may form a 3-, 4-, 5- or 6-memberedheteroalkyl or heteroaryl ring system which contains one or twoheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur; and

b) the bond between the ring carbons indicated as —C₁₄-C₁₅— in formula Imay be either a single bond or a double bond; and the further provisothat:

c) R7 is not hydrogen.

The invention also relates to a compound of formula I, wherein

each of R1, R2, R3 and R6 is —OH;

R4 and R5, together with the carbon atom to which they are bonded, forman epoxide;

R7 is the radical —S—CH₂—CHOH—COOH;

R8 is ═O;

R10 and R11 are each hydrogen;

and the bond between —C₁₄-C₁₅— is a single bond.

The invention also relates to optically pure compounds of the formula Iand to their stereoisomeric mixtures, such as enantiomeric mixtures anddiasteromeric mixtures, in any ratio to each other.

The term “halogen” is understood as meaning fluorine, chlorine, bromineor iodine. The term “(C₁-C₆)-alkyl” is understood as meaning hydrocarbonradicals whose carbon chain is straight-chain or branched and containsfrom 1 to 6 carbon atoms, for example methyl, ethyl, propyl, i-propyl,butyl, tertiary butyl, pentyl and hexyl. The term “(C₂-C₆)-alkenyl” isunderstood as meaning hydrocarbon radicals whose carbon chain isstraight-chain or branched and contains from 2 to 6 carbon atoms, andwhich exhibits one, two or three double bonds, for example the radicalsallyl, crotyl, 1-propenyl, penta-1,3-dienyl, pentenyl and hexenyl. Theterm “(C₂-C₆)-alkynyl” is understood as meaning hydrocarbon radicalswhose carbon chain is straight-chain or branched and contains from 2 to6 carbon atoms and which exhibits one or two triple bonds, for examplethe radicals propynyl, butynyl and pentynyl. The term “aryl” isunderstood as meaning the radicals phenyl, benzyl, 1-naphthyl and2-naphthyl. The expression “R4 and R5, together with the carbon atoms towhich they are in each case bonded, form a 3-, 4-, 5- or 6-membered ringsystem which is aromatic or saturated and which contains one or twoheteroatoms from the series oxygen, nitrogen or sulfur” is understood asmeaning radicals such as epoxide, aziridine, azetidine, azetine,pyrrole, pyrrolidine, pyridine, piperidine, tetrahydropyridine,pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine,imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, pyran,oxazole, isoxazole, 2-isoxazoline, isoxazolidine, morpholine,oxothiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline,isothiazolidine or thiomorpholine.

The invention furthermore relates to the compound of the formula II

In the description which follows, the compound of the formula II istermed thioperylenol (empirical formula: C₂₃H₂₀NO₉S; molecular weight472.47) and to the physiologically tolerated salts thereof.

The invention furthermore relates to a process for preparing a compoundof formula I, and/or a stereoisomeric form of a compound of the formulaI and/or mixtures of these forms in any ratio, and/or a physiologicallytolerated salt of a compound of formula I, which process comprises

a) culturing the microorganism DSM 14452, or its mutants or variants, inan aqueous nutrient medium and isolating and purifying the compoundthioperylenol, or

b) converting thioperylenol, by means of chemical derivatization, into acompound of the formula I, or

c) resolving a compound of the formula I, which has been prepared bymethods a) or b) and which, because of its chemical structure, appearsin enantiomeric forms, into the pure enantiomers by forming salts withenantiomerically pure acids or bases, by chromatography on chiralstationary phases or by derivatizing with chiral, enantiomerically purecompounds such as amino acids, separating the diastereomers which arethus obtained and eliminating the chiral auxiliary groups, or

d) either isolating the compound of the formula I which has beenprepared by the methods a), b) or c) in free form or, when acidic orbasic groups are present, converting it into physiologically toleratedsalts.

The microorganism DSM 14452 (internal designation ST003367) belongs tothe fungal group and possesses a white substrate mycelium and verylittle aerial mycelium and was deposited on Aug. 3, 2001, under theconditions of the Budapest Treaty, in the DSMZ-Deutsche Sammlung vonMikroorganismen und Zellkulturen [German collection of microorganismsand cell cultures] GmbH, Mascheroder Weg 1b, D-38124 Braunschweig, underthe number DSM 14452.

Variants of DSM 14452 are understood as being DSM 14452 strains whichhave been obtained by isolating individual colonies from a culture ofDSM 14452 on the proviso that they produce thioperylenol. Mutants of DSM14452 are understood as being DSM 14452 strains which have been obtainedfrom a culture of DSM 14452 after mutation, with the proviso that theyproduce thioperylenol. Mutants of DSM 14452 can be generated, in amanner known per se, by physical means, for example irradiation, such asultraviolet or X-ray radiation, or by using chemical mutagens, forexample ethyl methanesulfonate (EMS); 2-hydroxy-4-methoxybenzophenone(MOB) or N-methyl-N′-nitro-N-nitrosoguanidine (MNNG).

The mutants are found, for example, by taking samples from the culturemedium and determining the inhibitory effect of thioperylenol.

Thioperylenol is produced by culturing DSM 14452. The nutrient solutioncontains carbon sources, such as sucrose, corn starch, dextrose,lactose, D-mannitol, molasses or malt extract, and nitrogen sources,such as soybean flour, peanut flour, proteins, peptones, peptides,tryptones, meat extract, yeast extract or ammonium salts or nitrates.

The nutrient solution also contains inorganic salts such as sodiumhydrogen phosphate, sodium chloride, calcium chloride, calcium sulfate,calcium carbonate, magnesium sulfate or potassium hydrogen phosphate. Inaddition, it is also possible to add fat, such as methyl oleate orsoybean oil, to the nutrient medium. Besides that, trace elements, suchas iron salts, manganese salts, copper salts, zinc salts or cobaltsalts, or other metal salts, are also added.

A preferred nutrient solution contains from about 0.05% to about 5%,preferably from about 1% to about 3%, potato dextrose and from about0.05% to about 3%, preferably from about 0.05% to about 1%, yeastextract. The percentages relate to the weight of the total nutrientsolution.

DSM 14452 is cultured at temperatures of from about 18° C. to about 35°C., preferably at from about 23° C. to about 28° C., and at pH values offrom about 3 to about 10, preferably from about 5 to about 9,particularly preferably at values of from about 4 to about 6. Theculture is carried out aerobically, initially in shaking flasks and,after that, in a fermenter while stirring and aerating with air or pureoxygen. The microorganisms are cultured in the fermenters for a periodof from about 48 to about 720 hours, preferably of from about 72 toabout 144 hours.

The formation of thioperylenol reaches its maximum after from about 96to about 144 hours.

The fungal strain DSM 14452 also forms mixtures of several compounds offormula I in the nutrient solution. The quantitative proportion of thecompounds of formula I in the mixture can vary depending on thecomposition of the nutrient solution. In addition, the composition ofthe medium can be used to direct the synthesis of individual compoundsof formula I such that the microorganism either does not produceindividual compounds of formula I at all or only produces them in aquantity which is below the limit of detection.

Thioperylenol is either isolated directly from the nutrient solution orisolated after the cells have been separated off, for example by meansof centrifugation or filtration. The thioperylenol can be isolated byextracting with solvents or by adsorbing on resins such as XAD 16, HP20, MCI Gel® CHP20P or ion exchangers. It is purified, for example, bychromatography on adsorption resins such as on Diaion® HP-20 (MitsubishiCasei Corp., Tokyo), on Amberlite® XAD 7 (Rohm and Haas, USA), or onAmberchrom® CG (Toso Haas, Philadelphia, USA). The separations can becarried out over a wide pH range. The range of pH 1 to pH 9 ispreferred, with the range of pH 2 to pH 8 being particularly preferred.In addition to this, reverse phase supports, which are used within thecontext of high pressure liquid chromatography (HPLC), are alsosuitable. Another isolation method is that of using molecular sievessuch as Fractogel® TSK HW-40S or Sephadex® LH-20.

The microbiologically produced thioperylenol is used as the startingmaterial for preparing the thioperylenol derivative. The compounds offormula I are prepared in a manner known per se; for example, theepoxide group of the thioperylene can be converted by hydrolysis orsolvolysis into alcohols or esters. Epoxides are very reactive compoundswhich, in addition to water and acids, also add on other nucleophilicreagents, such as alcohols, thiols, amines and Grignard compounds, inthe presence of acidic or basic catalysts. The addition of hydrogencyanide leads further on to β-hydroxy-propionitrile derivatives. Inaddition to this, epoxides can be rearranged to givecarbonyl-derivatives, with this rearrangement being catalyzed, forexample, by Lewis acids. In addition, the reaction products can besubjected to further reactions. These reactions are known per se and aredescribed, for example, by Jerry March, Advanced Organic Chemistry, JohnWiley & Sons, 4^(th) Edition, 1992.

Other derivatives are obtained if the 3-thio-lactic acid radical of thethioperylenol is reacted reductively or oxidatively. It can also beadvantageous to use the sulfide as what is termed a leaving group andreplace it with other suitable radicals in a manner known from theliterature. In order to carry out reactions selectively, it can beadvantageous to introduce suitable protecting groups, in a manner knownper se, prior to the reaction. The protecting groups are eliminatedafter the reaction and the reaction product is then purified.

Pharmacologically tolerated salts of compounds of formula I areunderstood as being both inorganic and organic salts, as are describedin Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)).Physiologically tolerated salts are prepared in a manner known per sefrom compounds of formula I, including their stereoisomeric forms, whichare capable of forming salts. With basic reagents, such as hydroxides,carbonates, hydrogen carbonates, alcoholates and ammonia, or organicbases, for example, trimethylamine, triethylamine, ethanolamine ortriethanolamine, or else basic amino acids, for example, lysine,ornithine or arginine, the carboxylic acid forms stable alkali metalsalts, alkaline earth metal salts or, where appropriate, substitutedammonium salts. If a compound of formula I possesses basic groups, it isalso possible to prepare stable acid addition salts with strong acids.Both inorganic acids and organic acids, such as hydrochloric acid,hydrobromic acid, sulfuric acid, benzenesulfonic acid, phosphoric acid,methanesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonicacid, trifluoromethylsulfonic acid, cyclohexylamidosulfonic acid, aceticacid, oxalic acid, tartaric acid, succinic acid and trifluoroaceticacid, are suitable for this purpose.

The invention also relates to pharmaceuticals which are characterized byan effective content of at least one compound of the formula I and/or aphysiologically tolerated salt of the compound of the formula I and/oran optionally stereoisomeric form of the compound of the formula I,together with a pharmaceutically suitable and physiologically toleratedcarrier substance, additive and/or other active compounds and auxiliarysubstances.

On account of their pharmacological properties, the compounds of formulaI are suitable for the prophylaxis and therapy of all those diseases inwhich high blood platelet aggregations occur and which are caused bythrombus formation or embolisms. These diseases include, for example,myocardial infarction, unstable angina pectoris, stroke, transitoryischemic attacks and peripheral arterial occlusion diseases (peripheralvascular disease) such as intermittent claudication.

The invention also relates to the use of at least one compound offormula I and/or all stereoisomeric forms of the compounds of formula Iand/or mixtures of these forms in any ratio, and/or a physiologicallytolerated salt of the compound of the formula I, for producingpharmaceuticals for the prophylaxis and therapy of diseases in whichhigh blood platelet aggregations occur, where R1, R2, R3, R4, R5, R6,R7, R8, R10 and R11 R1, R2, R3, R4, R5, R6, R7, R8, R10 and R11 areindependently selected from the group consisting of

hydrogen;

(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of:

—CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted by one, two or three substituentsselected from the group consisting of halogen; —C(O)—OH; —C(O)—O—NH₂;—C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—NH—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—NH₂ and halogen;

(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straightenbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen;

(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen;

—O—R⁹, in which R⁹ is selected from the group consisting of:(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

—NH—R⁹, in which R⁹ is as defined above;

—NH—C(O)—H;

—NH—C(O)—R⁹, in which R⁹ is as defined above;

—NH-aryl, in which aryl is unsubstituted or independently substitutedone, two or three times by R⁹, in which R⁹ is as defined above:

═N—OH;

═N—O—R⁹, in which R⁹ is as defined above;

—S—H;

—S—R⁹, in which R⁹ is as defined above;

—S(O)—R⁹, in which R⁹ is as defined above;

—S(O)₂—R⁹, in which R⁹ is as defined above; and

—SO₂, with the following further alternatives to the foregoingdefinition:

a) either R4 and R5 or R10 and R11, together with the carbon atoms towhich they are, respectively, bonded, may form a 3-, 4-, 5- or6-membered heteroalkyl or heteroaryl ring system which contains one ortwo heteroatoms selected from the group consisting of oxygen, nitrogenand sulfur; and

b) the bond between the ring carbons indicated as —C₁₄-C₁₅— in formula Imay be either a single bond or a double bond; and the further provisothat:

c) R7 is not hydrogen.

The invention also relates to a process for producing a pharmaceutical,which process comprises bringing at least one compound of the formula I,together with a pharmaceutically suitable and physiologically toleratedexcipient and, where appropriate, other suitable active compounds,additives or auxiliary substances, into a suitable form foradministration.

Examples of suitable solid or galenic preparation forms are granules,powders, sugar-coated tablets, tablets, (micro)capsules, suppositories,syrups, juices, suspensions, emulsions, drops or injectable solutionsand preparations having a protracted release of the active compound, inthe production of which use is made of customary adjuvants such ascarrier substances, disintegrants, binders, coating agents, swellingagents, glidants or lubricants, flavorings, sweeteners and solubilizers.Frequently employed auxiliary substances which may be mentioned are:magnesium carbonate, titanium dioxide, lactose, mannitol and othersugars, talc, milk protein, gelatin, starch, cellulose and itsderivatives, animal and vegetable oils, such as cod liver oil, sunfloweroil, peanut oil or sesame oil, polyethylene glycol and solvents, such assterile water and monohydric or polyhydric alcohols, such as glycerol.

The pharmaceutical preparations are preferably produced and administeredin dosage units, with each unit containing, as the active constituent, aparticular dose of the compound of the formula I according to theinvention. In the case of solid dosage units, such as tablets, capsules,sugar-coated tablets or suppositories, this dose can be from 0.1 mg/kgof body weight to 1,000 mg/kg of body weight, preferably from 0.2 mg/kgof body weight to 100 mg/kg of body weight. They are expedientlyadministered in dosage units which contain at least the effective dailyquantity of the compound of the formula I, for example up to 1000 mg,preferably, however, from about 50 to 300 mg and, in the case ofinjection solutions in ampule form, up to about 300 mg, preferably,however, from about 10 to 100 mg.

Daily doses of from about 20 mg to 1,000 mg, preferably from about 100mg to 500 mg, of active compound, depending on the activity of thecompound according to formula I, are indicated for treating an adultpatient of about 70 kg in weight. However, it may possibly also beappropriate to use higher or lower daily doses. The daily dose can beadministered either by means of a once-only administration in the formof a single dosage unit or of several smaller dosage units or by meansof a repeated administration of subdivided doses at particularintervals.

The microorganism DSM 14452 is also part of the subject matter of theinvention.

The following examples are intended to illustrate the invention withoutthereby restricting the scope of the invention in any way.

EXAMPLE 1 Preparing a Glycerol Culture of the Fungal Strain DSM 14452

30 ml of nutrient solution (malt extract, 2.0%, yeast extract, 0.2%,glucose, 1.0%, (NH₄)₂HPO₄, 0.05%, pH 6.0) in a sterile 100 ml Erlenmeyerflask were inoculated with the fungal strain ST 003367, DSM 14452, andincubated at 25° C. and 140 revolutions per minute (rpm) on a rotatingshaker for 6 days. 1.5 ml of this culture were subsequently diluted with2.5 ml of 80% glycerol and stored at −135° C.

EXAMPLE 2 Preparing a Preliminary Culture of the Fungus DSM 14452 (in anErlenmeyer Flask)

100 ml of nutrient solution (malt extract, 2.0%, yeast extract, 0.2%,glucose, 1.0%, (NH₄)₂HPO₄, 0.05%, pH 6) in a sterile 300 ml Erlenmeyerflask were inoculated with the fungal strain ST 003367, DSM 14452, andincubated at 25° C. and 140 rpm on a rotating shaker for 4 days. 2 ml ofthis preliminary culture were subsequently required for preparing themain cultures.

EXAMPLE 3 Preparing Thioperylenol by Culturing the Fungal Strain DSM14452

In the flask:

A sterile 300 ml Erlenmeyer flask containing 100 ml of the followingnutrient solution: potato dextrose, 2.4%, yeast extract, 0.2%, pH 5.1,was inoculated with a culture which had been grown on a sloping tube(same nutrient solution but containing 2% agar), or with 2 ml of apreliminary culture, as described in example 2, and incubated at 25° C.and 140 rpm on a shaker. The maximum production of one or more compoundsof the formula I was achieved after about 96 hours.

In the fermenter:

The preliminary culture of the strain ST 003367, DSM 14452, was grown at25° C. and 140 rpm in a 2 L Erlenmeyer flask (volume in the flask, 500mL). The fermenter was inoculated after 72 h. The strain was fermentedin 8 L fermenters. The conditions for the fermentation were set asfollows and led to the production of the compound according to theinvention thioperylenol:

Temperature=25° C.; gassing=0.5 wm; rotational speed=200-220 revolutionsper minute (rpm); inoculum=6%; culturing time=96 hours (h).

Nutrient Media:

Preliminary culture Malt extract 20 g/L Yeast extract 2 g/L Glucose 10g/L (NH₄)₂PO₄ 0.5 g/l Main culture Potato dextrose broth 24 g/L Yeastextract 2 g/L Desmophene 1.25 mL/L

It was possible to suppress foam formation by repeatedly addingethanolic polyol solution. The maximum production was reached after fromabout 96 to 144 hours.

EXAMPLE 4 Isolating the Natural Product Thioperylenol

15 liters of the culture solution obtained in accordance with example 3were freed from the cell mass by centrifugation. The mycelium (1.5liters) is extracted with 5 liters of methanol. The clear alcoholicphase was concentrated down to about 2 liters under reduced pressure andcombined with the culture filtrate. The turbid aqueous solution was thenloaded onto a 1 L-capacity column which was filled with the absorptionresin MCI Gel® CHP20P. Column dimensions: width x height: 6 cm×35 cm.The column was eluted with a solvent gradient of 0.1% ammonium formatebuffer, pH 4.5, in water after 2-propanol. The column effluent (60mL/minute) was collected in fractions of in each case 220 mL. Thethioperylenol-containing fractions 21 and 22, which were tested by HPLCanalyses, were collected and concentrated under reduced pressure. Thethioperylenol was obtained in pure form by repeated preparative HPLC onSP 250/21 NUCLEOSIL 100-7 C18 HD® columns (Macherey-Nagel, Düren) usingthe eluent 0.1% ammonium formate, pH 4.8, in water/95% acetonitrile in agradient method. The flow rate through the column was 25 mL/minute andthe thioperylenol was eluted from the separating column with anacetonitrile content of about 25%. 10 mg of crystalline thioperylenolwere obtained by slowly concentrating under reduced pressure.

EXAMPLE 5 High-Pressure Liquid Chromatography (HPLC) of theThioperylenol

Column: YMC-Pack Pro C18 ®, AS-303, 250 × 4.6 mm, S-5 μm; Mobile Phase:0 to 2 minutes: 0.02% trifluoroacetic acid (TFA), 2 to 20 minutes: 0% to100% acetonitrile in 0.1% TFA, 20 to 25 minutes: 100% acetonitrile. Flowrate: 1 mL per minute,

Detection by UV Absorption at 210 nm.

The retention time for thioperylenol was found to be 12.1 minutes.

EXAMPLE 6 Properties of Thioperylenol

The physicochemical and spectroscopic properties of thioperylenol can besummarized as follows:

Appearance:

Brownish crystals which are soluble in medium-polar and polar organicsolvents and soluble in aqueous neutral buffers. Stable in neutral andmildly acidic, non-oxidizing medium but unstable in strongly acidic andstrongly alkaline solution.

Empirical formula: C₂₃H₂₀O₉S, molecular weight: 472.47 ¹H and ¹³C NMR:see table 1;

UV maxima in water/acetonitrile (1 to 1), pH 3.0: 216 nm, 259 nm, 292 nmand 383 nm.

TABLE 1 Chemical shifts of V-2474 in DMSO at 300K. Position ¹H ¹³C 1 —160.14 2 7.01 118.22 3 8.05 132.57 4 — 125.12 5 — 137.09 6 — 113.86 7 —122.82 8 7.53 123.75 9 6.79 113.50 10 — 156.37 11 — 122.66 12 — 128.0813 — 204.10 14 3.62/3.06 ˜39.1 15 4.29 46.56 16 — 70.80 17 3.64 41.35 183.93 49.15 19 3.44 55.30 20 5.11 59.67 21 2.92/2.76 36.23 22 3.72 72.9623 — 174.38

EXAMPLE 7 Mass Spectrometric Characterization of Thioperylenol

Thioperylenol is assigned the mass of 472 on the basis of the followingfindings: the ESI⁺ spectrum gave weak peaks at 490 amu (M+NH₄)⁺ and 962amu (2M+NH₄)⁺. The ESI⁻ spectrum gave a peak, inter alia, at 471 amu(M−H)⁻.

Using an FTICR mass spectrometer, a peak was observed, inter alia, at569.0525 amu in the ESI⁻ mode and in the added presence of phosphoricacid. The measured value agrees well with that calculated for(M+H₂PO₄)⁻=C₂₃H₂₂O₁₃PS=569.0524 amu (0.2 ppm difference). MS/MSexperiments using an FTICR mass spectrometer led to the followingfragmentations in the ESI⁻ mode: 471 amu to 349 amu (—C₃H₆O₃S), 331 amu(—C₃H₈O₄S), 313 amu (—C₃H₁₀O₅S), 303 amu (—C₄H₈O₅S), 285 amu(—C₄H₁₀O₆S), 261 amu (—C₆H₁₀O₆S) and smaller fragments.

Pharmacological Examples

The inhibition of platelet aggregation can be measured, inter alia, bydetermining platelet aggregation turbimetrically as described by Born(Born, GV, Nature, 1962,194: 927-929).

Principle of the test: the method is based on the property that theoptical density of a particle suspension depends on the number ofparticles and not on their size. After a platelet suspension has beenstimulated, the platelets begin to aggregate. This leads to theappearance of relatively large platelet aggregates and to an increase inlight transmission. This increase is registered photometrically, andrecorded in curve form, continuously. The degrees to which thethrombocytes can be aggregated, or to which this aggregation can beinhibited, can be deduced from the changes in light transmission. Themethod of staining cells with calcein was used for determiningcytotoxicity (Hollo Z et al., Biochim Biophys Acta 11;1191(2):384-8,1994). Living cells incorporate the substrate calcein acetoxymethylester (C-AM), which is hydrolyzed in the cells by nonspecific esterases.C-AM is colorless and does not fluoresce. In the living cell, it isconverted into the fluorescent hydrolysis product and the vitality ofthe cells can be measured on the basis of the fluorescence (λ_(ex):485nm/λ_(em):538 nm).

By way of example, Table 2 summarizes the inhibitory effects of somehydroperylene derivatives as IC₅₀ values. The IC₅₀ value indicates theconcentration which inhibits thrombocyte aggregation by 50% underdefined conditions.

TABLE 2 The concentrations of some hydroperylene derivatives whichinhibit thrombocyte aggregation by 50% (IC₅₀). Compound IC₅₀ (plateletaggregation) IC₅₀ (toxicity) Thioperylenol 7.2 μM 61 μM Alterperylenol1.6 μM >100 μM Altertoxin I 29 μM >100 μM Altertoxin II 2.6 μM 10 μMAltertoxin III 6.1 μM 20 μM

As can be seen from the table, in addition to inhibiting thrombocyteaggregation, some of the hydroperylene derivatives also exhibit asubstantial degree of cell toxicity. The cell toxicity is particularlymarked in the case of compounds which carry epoxide groups. For thisreason, those compounds of the formula I which, while possessing aninhibitory effect on platelet aggregation, are relatively nontoxic areparticularly valuable. Preference is consequently given tohydroperylenol derivatives which are epoxide-free.

EXAMPLE 8 Test for Inhibition of Thrombocyte Aggregation

The following reagents are required for implementing the thrombocyteaggregation test:

Materials Supplier Catalogue No. Water tissue culture grade SigmaW-3500  NaCl Merck 1.06404 KCl Merck 1.04933 CaCl₂ Merck 1.02083Albumin, bovine (BSA) Sigma A-6003 Calcein AM Molecular Probes C-1430Collagen reagent Nycomed 5368 Human alpha Thrombin HaemochromDiagnostica HT1002A

The assay was carried out as follows:

Tyrode Buffer:

NaCl 120 mM KCl 2.6 mM NaHCO3 12 mM NaH₂PO₄ × H₂O 0.39 mM Hepes 10 mMGlucose 5.5 mM BSA 0.35%

Add fresh glucose and BSA daily

Adjust pH to 7.4

Calcein AM: 1 mg of Calcein AM in 1 ml of DMSO (1 mM)

Human α-thrombin (stock solution): 1000 units in 1 ml of 0.9% NaCl

Final concentration of activator: 0.05 U of thrombin/ml or 1 μg ofcollagen/ml

Wortmannin, stock solution: 1 mg in 233.43 μl of DMSO (10 mM).

Aggregation in Aggregometer (PAP 4)

Cell number, 3×10⁵ thrombocytes/μl

Mixture in siliconized glass microtubes

Total volume, 400 μl/tube

Per Microtube:

320 μl of thrombocytes

20 μl of 10 mM CaCl₂ (f.c. 0.5 mM)

20 μl of test substance

40 μl of agonist

Controls:

Blank: 400 μl of buffer (Tyrode, 0.35% BSA) Negative control: 320 μl ofthrombocytes 40 μl of CaCl₂ 5 mM (f.c. 0.5 mM) 40 μl of buffer Positivecontrol: 320 μl of buffer 40 μl of 5 mM CaCl₂ (f.c. 0.5 mM) 40 μl ofactivator

The blank value for the channels of the aggregometer is first of alladjusted using buffer. The thrombocytes are then pipetted intomicrotubes and, after the thrombocytes have been added, heated at 37° C.for a few minutes in the aggregometer. After a magnetic stirrer has beenadded to each reaction tube, the substances, and CaCl₂, are added and astart is made in recording the course of the curve in the aggregometer.After 2 minutes of incubation, the activator, or buffer in the case ofthe control, is added. The course of the curve is then recorded for afurther 6 min at 37° C. and at a stirrer speed of 1050 revolutions perminute.

What is claimed is:
 1. A compound of formula I

including all stereoisomeric forms of said compound of formula I,mixtures of said forms and compounds in any ratio, and/physiologicallytolerated salts thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R10and R11 are independently selected from the group consisting ofhydrogen; (C₁-C₆)-alkyl, in which alkyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted by one, two or three substituents selected from the groupconsisting of halogen; —C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, inwhich alkyl is a straight or branched chain; —NH—(C₁-C₆)-alkyl, in whichalkyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl,in which alkyl is a straight or branched chain; —NH—(C₂-C₆)-alkenyl, inwhich alkenyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl,in which alkyl is a straight or branched chain; —NH—(C₂-C₆)-alkynyl, inwhich alkynyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl,in which alkyl is a straight or branched chain; —NH₂ and halogen;(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen; (C₂-C₆)-alkynyl, in which alkynyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straightor branched chain and is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:—CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; —O—R⁹, in which R⁹ isselected from the group consisting of: (C₁-C₆)-alkyl, in which alkyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straightor branched chain and is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:—CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straightor branched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; (C₂-C₆)-alkenyl, inwhich alkenyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; -aryl, in which aryl is unsubstitutedor substituted by one, two or three substituents independently selectedfrom the group consisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain and is substituted one, two or three times byhalogen; —C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; (C₂-C₆)-alkynyl, inwhich alkynyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; -aryl, in which aryl is unsubstitutedor substituted by one, two or three substituents independently selectedfrom the group consisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain and is substituted one, two or three times byhalogen; —C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; —NH—R⁹, in which R⁹is as defined above; —NH—C(O)—H; —NH—C(O)—R⁹, in which R⁹ is as definedabove; —NH-aryl, in which aryl is unsubstituted or independentlysubstituted one, two or three times by R⁹, in which R⁹ is as definedabove: ═N—OH; ═N—O—R⁹, in which R⁹ is as defined above; —S—H; —S—R⁹, inwhich R⁹ is as defined above; —S(O)—R⁹, in which R⁹ is as defined above;—S(O)₂—R⁹, in which R⁹ is as defined above; and —SO₂, with the followingfurther alternatives to the foregoing definition: a) either R4 and R5 orR10 and R11, together with the carbon atoms to which theyare,respectively, bonded, may form a 3-, 4-, 5- or 6-memberedheteroalkyl or heteroaryl ring system which contains one or twoheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur; and b) the bond between the ring carbons indicated as —C₁₄-C₁₅—in formula I may be either a single bond or a double bond; and thefurther proviso that: c) R7 is not hydrogen.
 2. A compound of theformula I as claimed in claim 1, wherein a) each of R1, R2, R3 and R6 is—OH, b) R4 and R5, together with the carbon atoms to which they arebonded, form an epoxide, c) R7 is the radical —S—CH₂—CHOH—COOH, d) R8 is═O, e) each of R10 and R11 is hydrogen atom; and f) the bond between thering carbons designated as —C₁₄-C₁₅— is a single bond, and/orphysiologically tolerated salts thereof of the compound of the formulaI.
 3. A compound as claimed in claim 2, which has the structure offormula II


4. A process for preparing a compound of formula I as claimed in claim1, which comprises a) culturing the microorganism DSM 14452, or a mutantor variant thereof, in an aqueous nutrient medium; b) isolating from theculture medium of step a) the compound thioperylenol; c) purifying thethiophenyl thus obtained; d) converting thioperylenol, whether or notobtained by the foregoing steps, by means of chemical derivatization,into a compound of the formula I; e) if necessary, i) resolving thecompound of the formula I so obtained, which, because of its chemicalstructure, appears in enantiomeric forms, into its pure enantiomerseither by forming salts with enantiomerically pure acids or bases, or bychromatography on chiral stationary phases or by derivatizing withchiral, enantiomerically pure compounds, such as amino acids, ii)separating the diastereomers which are thus obtained and iii)eliminating the chiral auxiliary groups; and f) optionally, eitherisolating the compound of the formula I which has been thus prepared infree form or, when acidic or basic groups are present, converting itinto a physiologically tolerated salts.
 5. A pharmaceutical compositionwhich contains a therapeutically effective amount of at least onecompound as claimed in claim 1, together with a pharmaceuticallysuitable and physiologically tolerated carrier substance or additiveand/or other active compounds and auxiliary substances.
 6. A method oftreating or preventing diseases in which high blood plateletaggregations occur, comprising administering to a mammal in need thereofan effective amount of a compound of claim 1 in pharmaceuticallyacceptable form.
 7. The method of claim 6 wherein said compound is asdefined in claim
 2. 8. The method of claim 6, wherein said compound isselected from the group consisting of: thioperylenol, a compound offormula I, in which: R1, R2, R3 and R6 are, in each case, —OH; R4 andR5, together with the carbon atoms to which they are in each casebonded, form an epoxide; R7 is the radical —S—CH₂—CHOH—COOH; R8 is ═O;R10 and R11 are, in each case, hydrogen; and the bond between —C₁₄-C₁₅—is a single bond; alterperylenol, a compound of formula I, in which R1,R2, R5 and R6 are, in each case, —OH; R3 and R8 are, in each case, ═O;R4, R7, R10 and R11 are, in each case, hydrogen; and the bond between—C₁₄-C₁₅— is a double bond; altertoxin I, a compound of formula I inwhich R1, R2, R5 and R6 are, in each case, —OH; R3 and R8 are, in eachcase, ═O; R4, R7, R10 and R11 are, in each case, hydrogen; and the bondbetween —C₁₄-C₁₅— is a single bond; altertoxin II, a compound of formulaI, in which R1, R2 and R6 are, in each case, —OH; R3 and R8 are in eachcase ═O; R4 and R5, together with the carbon atoms to which they are ineach case bonded, form an epoxide; R7, R10 and R11 are, in each case,hydrogen; and the bond between —C₁₄-C₁₅— is a single bond; andaltertoxin III, a compound of formula I, in which R1 and R3 are, in eachcase, ═O, R2 and R8 are, in each case, —OH; R4 and R5 and R10 and R11,together with the carbon atoms to which they are in each case bonded,form an epoxide; R6 and R7 are, in each case, hydrogen; and the bondbetween —C₁₄-C₁₅— is a single bond.
 9. The method of claim 6, whereinsaid disease in which high blood platelet aggregations occur is selectedfrom the group consisting of myocardial infarction, unstable anginapectoris, stroke, transitory ischemic attacks and peripheral arterialocclusion diseases such as intermittent claudication.